Non-small cell lung cancer (NSCLC) patients have a dismal five year survival rate of ~15%. Antitumor agents that target unique protein markers to kill NSCLC cells irrespective of growth state, and target primary and metastatic cells, are desperately needed. We completed all the proposed Aims in the prior granting period and elucidated the mechanism of action of -lapachone (-lap) alone against NSCLC cells. -Lap was selectively efficacious for NSCLCs, in which >80% tumors had 5- to >100-fold endogenous overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1). -Lap kills NSCLC cells through an NQO1/ROS/Ca2+ER/PARP1 hyperactivation pathway, leading to -calpain cell death. To overcome solubility and normal tissue toxicity problems, various -lap delivery methods were developed. Arq501 (-lap in hydroxypropyl--cyclodextrin, Arqule Chem. Co., MA) entered several Phase II clinical trials based on our work. Several novel nanoparticle micelle delivery systems that will increased the efficacy of -lap or pH-sensitive -lap prodrugs alone, or in combination with radiation therapy, will be explored in this competitive renewal. We hypothesize that cancer-targeted, pH-sensitive nanoparticle micelles loaded with -lap or -lap pH-sensitive prodrugs can be used to significantly increase the efficacy of -lap alone, and in combination with ionizing radiation (IR) therapy (XRT). IR + -lap synergy results from meeting a accumulative damage threshold, that in turn stimulates the NQO1/ROS/ Ca2+ER/PARP1 hyperactivation pathway that activates -calpain, a programmed necrotic/apoptotic pathway unique to -lap cell killing. Three Aims will be completed: Aim 1. To elucidate the mechanism of action of -lap as a radiosensitizer. (Years 1-5). Aim 2: To design and develop stealth, cancer-targeting nanoparticle micelles loaded with -lap or pH- sensitive -lap prodrugs to efficaciously treat human NSCLCs. (Years 1-5). Aim 3: To elucidate and optimize the pharmacokinetics and antitumor activity in vivo of -lap-loaded nanoparticle micelles alone and with XRT against NSCLCs as xenograft or orthotopic models (Years 1-5). The ultimate goal of this grant is to develop a platform of -lap compounds delivered by nanoparticle micelles that can efficacious treat NSCLC by exploiting their unique overexpression of NQO1. PUBLIC HEALTH RELEVANCE: Patients with nonsmall cell lung cancer (NSCLC) have little hope of being cured of their diseases, with five-year survival rates at only 15%. This competitive renewal will build on the many findings of the prior grant, including: (i) evaluation and demonstration of elevated (5- to 100-fold) NQO1 levels in NSCLC populations from Hong Kong and New York; (ii) elucidation of -lap mechanism of action; (iii) development of novel -lap-encoded nanoparticles; (iv) development of pH sensitive -lap prodrugs; (v) efficacious antitumor activity of -lap against orthotopic, as well as xenograft models of A549 NSCLCs; and (vi) development of functionalized nanoparticles that can target the angiogenic endothelial cells that innervate the tumor neovasculature. The ultimate goal of these studies is to develop a nanoparticle platform for the cancer-targeted delivery of -lap and its pH-sensitive prodrugs for the eradication of nonsmall cell lung cancers.